Oritavancin diphosphate (oritavancin; also known as NDISACC-(4-(4-chlorophenyl)benzyl)A82846B and LY333328) is a semi-synthetic lipoglycopeptide derivative of a naturally occurring glycopeptide. Its structure confers potent antibacterial activity against gram-positive bacteria, including vancomycin-resistant enterococci (VRE), methicillin- and vancomycin-resistant staphylococci, and penicillin-resistant streptococci. The rapidity of its bactericidal activity against exponentially-growing S. aureus (≧3-log reduction within 15 minutes to 2 hours against MSSA, MRSA, and VRSA) is one of the features that distinguishes it from the prototypic glycopeptide vancomycin (McKay et al., J Antimicrob Chemother. 63(6):1191-9 (2009), Epub 2009 Apr. 15).
Oritavancin inhibits the synthesis of peptidoglycan, the major structural component of the bacterial cell wall by a mechanism that is shared with glycopeptides, such as vancomycin (Allen et al., Antimicrob Agents Chemother 41(1):66-71 (1997); Cegelski et al., J Mol Biol 357:1253-1262 (2006); Arhin et al., Poster C1-1471: Mechanisms of action of oritavancin in Staphylococcus aureus [poster]. 47th Intersci Conf Antimicro Agents Chemo, Sep. 17-20, 2007, Chicago, Ill.). Oritavancin, like vancomycin, binds to the Acyl-D-Alanyl-D-Alanine terminus of the peptidoglycan precursor, lipid-bound N-acetyl-glucosamine-N-acetyl-muramic acid-pentapeptide (Reynolds, Eur J Clin Microbiol Infect Dis 8(11):943-950 (1989); Nicas and Allen, Resistance and mechanism of action. In: Nagarajan R, editor. Glycopeptide antibiotics. New York: Marcel Dekker 195-215 (1994); Allen et al., Antimicrob Agents Chemother 40(10):2356-2362 (1996); Allen and Nicas, FEMS Microbiology Reviews 26:511-532 (2003); Kim et al., Biochemistry 45:5235-5250 (2006)). However, oritavancin inhibits cell wall biosynthesis even when the substrate is the altered peptidoglycan precursor that is present in VRE and vancomycin-resistant S. aureus (VRSA). Thus, the spectrum of oritavancin antibacterial activity extends beyond that of vancomycin to include glycopeptide-resistant enterococci and staphylococci (Ward et al., Expert Opin Investig Drugs 15:417-429 (2006); Scheinfeld, J Drugs Dermatol 6:97-103 (2007)). Oritavancin may inhibit resistant bacteria by interacting directly with bacterial proteins in the transglycosylation step of cell wall biosynthesis (Goldman and Gange, Curr Med Chem 7(8):801-820 (2000); Halliday et al., Biochem Pharmacol 71(7):957-967 (2006); Wang et al., Poster C1-1474: Probing the mechanism of inhibition of bacterial peptidoglycan glycotransferases by glycopeptide analogs. 47th Intersci Conf Antimicro Agents Chemo, Sep. 17-20, 2007). Oritavancin also collapses transmembrane potential in gram positive bacteria, leading to rapid killing (McKay et al., Poster C1-682: Oritavancin disrupts transmembrane potential and membrane integrity concomitantly with cell killing in Staphylococcus aureus and vancomycin-resistant Enterococci. 46th Intersci Conf Antimicro Agents Chemo, San Francisco, Calif., Sep. 27-30, 2006). These multiple effects contribute to the rapid bactericidal activity of oritavancin.
Polymyxins are polypeptide antibiotics that include five chemically different compounds (Polymyxins A-E) (Balaji V et al., Polymyxins: Antimicrobial susceptibility concerns and therapeutic options. Indian J Med Microbiol 2011; 29:230-42). Polymyxin B was first isolated in Japan in 1949 and it is derived from Bacillus polymyxa. Polymyxin E, also known as colistin, can be obtained from Bacillus polymyxa subspecies colistinus. Polymyxins B and E have both been used in clinical practice for over 50 years, while polymyxin A, C and D are not used to treat humans because of toxicity concerns. Polymyxin E (colistin) was initially used in intravenous and intramuscular formulations for the treatment of gram-negative bacterial infections, falling out of favor in the 1970s upon the introduction of aminoglycosides which exhibit less toxicity.
Polymyxins are surface-acting ampipathic agents (Balaji V. et al., Polymyxins: Antimicrobial susceptibility concerns and therapeutic options. Indian J Med Microbiol 2011; 29:230-42). Each molecule of polymyxin includes a cationic polypeptide ring with a lipophilic fatty acid side chain (Kwa A L et al., Polymyxins: A review of the current status including recent developments. Ann Acad Med Singapore 2008; 37:870-83). The polypeptide ring binds with the anionic phosphate moieties in the bacterial cell membrane, displacing Ca2+ and Mg2+, which are needed for membrane integrity. This results in increased permeability of the cell membrane causing leakage of cellular contents, leading to cell death (Groisman E A et al., Regulation of polymyxin resistance and adaptation to low-Mg2+ environments. J Bacteriol 1997; 179:7040-5). The disruption of membrane integrity also increases the susceptibility of the organism to hydrophilic antibiotics such as rifampicin, carbapenems, glycopeptides and tetracyclines, thus paving the way for both gram-negative and gram-positive antimicrobial synergistic combination therapy (Conrad R S et al., Fatty acid alterations and polymyxin B binding by lipopolysaccharides from Pseudomonas aeruginosa adapted to polymyxin B resistance. Antimicrob Agents Chemother 1989; 33:1724-8).
The development of additional combinations of antibiotics that can be used in the treatment of bacterial infections will add to the arsenal of therapeutic options available to clinicians. The present application is directed to this and other important goals.